Parkinson's disease patients experience profound depletion of striatal dopamine (DA) due to degeneration of the nigrostriatal DA pathway. The predominant treatment for the past 30 years has been the DA precursor, L-dopa. While this strategy improves motor deficits, it has no effect on the underlying degenerative process, and indeed can have the additional unwanted side-effect of inducing dyskinesia. A possible alternative therapy, with neuroprotective ability appears to be use of antagonists of a specific class of adenosine receptors, A2A. These agents appear to have both motor-activating properties and preliminary data suggest they may also attenuate MPTP-induced DA neurotoxicity and prevent the locomotor stimulation that occurs with chronic DA receptor stimulation. The proposed studies will systematically investigate the novel motor and neuroprotective effects of A2A receptor antagonists. Methods center around pharmacological studies and use of genetic knockout (KO) approaches. There are three specific aims: 1) to test the hypothesis that A2A inactivation enhances motor function through D2R-dependent and independent mechanisms using A2AR-KO, D2R-KO and double KO mice; 2) to test the hypothesis that A2AR inactivation prevents the development of chronic L-dopa-induced rotational motor sensitization in unilateral 6-OHDA-lesioned mice; and 3) to characterize the role of V in MPTP-induced neurotoxicity by establishing the potency, "therapeutic window" and by "analyzing synergy between A2AR activation and inactivation;" in addition, the effect of A2AR agents on MPTP metabolism in vivo and in cell culture will also be examined to investigate the neurochemical mechanisms of protection by A2AR inactivation.